Josep Mallolas Hospital Clínic Barcelona

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Nuevos paradigmas en la infección VIH Josep Mallolas Hospital Clínic Barcelona

1. Do you believe, I have to start ARV therapy?

Incidence and Mortality of AIDS in Spain

HIV and NON-AIDS complications

HIV and NON-AIDS complications

HIV and NON-AIDS complications

HIV and NON-AIDS complications

2.- What is my life expectancy?

Improve Survival in HIV Patients CD4 count 500mm 3 is associated with standard mortality ratio (SMR) similar to general population 1 8 CD4: 350 to 499/mm 3 CD4 500/mm 3 7 6 SMR (CI) 5 4 3 2 1 0 0 1 2 3 4 5 6 7 8 Time of truncation after initiation of cart (years) Lewden C, et al. J Acquir Immune Defic Syndr 2007;46(1):72 77

3.- Can I cure my HIV infection?

When start ARV Therapy? Hit hard and hit early David Ho, 1996

Slow decay of latently infected CD4 + T cells t ½ = 44.2 months Frequ uency (per 10 6 cells s) 10000 1000 100 10 1 0.1 0.01 0.001 - Time to eradication > 73.4 years 0.0001 0.00001 0 1 2 3 4 5 6 7 Time on HAART (years) Finzi et al., Science, 1997 Wong et al. Science, 1997 Finzi et al., Nature Med., 1999 Chun et al., Nature Med., 1995 Chun et al., PNAS, 1997 Siliciano et al., Nature Med., 2003 Chun et al., Nature, 1997

ARV Armentarium 2009 ZDV ddi ddc d4t NVP 3TC DLV ABC EFV TDF FTC RAL ETR 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 NRTI SQV NFV LPV/r NNRTI PI Entry inhibitor Integrase inhibitor RTV IDV APV ATV FPV ENF TPV DRV MVC 25 unique ARV agents approved, 6 different classes

Typical Disease Progression in an Untreated HIV-Infected Infected Patient Pantaleo G et al. N Engl J Med. 1993;328:327-35. Copyright 1993 Massachusetts Medical Society. All rights reserved.

HIV Lifecycle Phases: binding and entry, reverse transcription, replication, budding, and maturation Reverse Transcriptions Act Here 6. Release Protein Inhibitors Act Here 1. Attachment 3. Transcription 2. Entry 4. Integration 7. Maturation 5. Polyprotein Production

4.- So, what treatment do you suggest?

HAART: Studies in Naïve patients With > 65% Response (VL < 50 at Wk 48) COMBINE (NVP + ZDV/3TC) 2NN (NVP BID + d4t + 3TC) ZODIAC (EFV + ABC QD + 3TC) M98-863 (LPV/RTV + d4t + 3TC) ZODIAC (EFV + ABC + 3TC) CNA30024 (EFV + ZDV + 3TC) 2NN (NVP QD + d4t + 3TC) 2NN (EFV + d4t + 3TC) CNA30024 (EFV + ABC + 3TC) M02-418 (LPV/RTV + FTC + TDF QD) FTC301 (EFV + FTC + ddi QD) DMP266-043 (EFV + D4T + 3TC) CLASS (EFV + ABC + 3TC) ANRS 12-04 (EFV + ddi + 3TC) M97-720 (LPV/RTV + d4t + 3TC) Dart 1 (EFV + ddi EC + 3TC) GS903 (EFV + d4t + 3TC) GS903 (EFV + TDF + 3TC) ANRS 091 (EFV + ddi + FTC) 30 NNRTI Boosted PI 40 50 60 70 80 90 100 Percentage With HIV-1 RNA < 50 copies/ml at Week 48 Bartlett JA, et al. AIDS. 2006;20:2051-2064.

HAART is effective! Recent Randomized ARV Trials Proportion with VL <50 copies/ml Week 48 (ITT) Naïve Trials Experienced Trials Gemini 64-65% Benchmrk 64% KLEAN 65-66% 66% Victor E1 (Wk 24) 64% ACTG 5142 (Wk 96) 77-89% Motivate 42-47% Artemis 78-84% Power 46% Merit 65-69% Duet 60-61% MK 004 87% TITAN 61-70% Castle 76-78% HEAT 67-68% Walmsley EACS, 2007, Eron, Lancet, 2007; Ridler, WAC, 2006; Clumeck, EACS, 2007; Saag, IAS, 2007; Markowitz, 8,JAIDS, 2007; y,,,, ;,, ;,, ; g,, ;,,, ; Molina, CROI, 2008; Smith CROI, 2008, Cooper, CROI 2008, Steigbigel, CROI 2008, Zingman, CROI 2008; Lalezari ICAAC 2007, Falkenheuer, EACS, 2007; Lazzarin, Lancet, 2007; Haubrich, CROI, 2008; Johnson CROI 2008; Madruga Lancet, 2007

Safety and Tolerability of Many Current Regimens Are Excellent Study Drug regimen Discontinuations Due to AEs,* % AI424-089 [1] GS934 [2] ATV + d4t + 3TC ATV/RTV + d4t + 3TC EFV + TDF + FTC EFV + ZDV/3TC KLEAN [3] FPV/RTV + ABC/3TC 12 LPV/RTV + ABC/3TC 10 ARTEMIS [4] CASTLE [5] DRV/RTV + TDF/FTC LPV/RTV + TDF/FTC ATV/RTV + TDF/FTC LPV/RTV + TDF/FTC HEAT [6] ABC/3TC + LPV/RTV 4 TDF/FTC + LPV/RTV 6 GEMINI [7] SQV/RTV + TDF/FTC LPV/RTV + TDF/FTC 3 8 5 11 3 7 2 3 4 7 1. Malan N, et al. IAS 2007. Abstract WEPEB024. 2. Arribas JR, et al. IAS 2007. Abstract WEPEB029. 3. Eron J Jr, et al. Lancet. 2006;368:476-482. 4. DeJesus E, et al. ICAAC 2007. Abstract 718-b. 5. Molina JM, et al. CROI 2008. Abstract 37. 6. Smith K, et al. CROI 2008. Abstract 774. 7. Walmsley SL, et al. EACS 2007. Abstract PS1.4.

We have better and more tolerable therapy It appears we have: - Less short term toxicity-diarrhoea, dyslipidemia - Less long term toxicities such as lipodystrophy - Better formulations - easier to take - lower pill burdens-one pill once a day - no refrigeration

When to start ARV Therapy? Late clinical i l stage Initial clinical stage < 200 High HIV viral load 20 0 CD4 > 35 500 0 Low HIV viral load

ACTG 5202: ABC/3TC vs TDF/FTC + EFV or ATV/RTV Randomized, double-blind, open-label phase IIIb study Stratified by HIV 1 RNA Week 96 Stratified by HIV-1 RNA < or 100,000 copies/ml primary endpoint TDF/FTC* 300/200 mg QD + EFV 600 mg QD *Double blind. Open label. HIV-infected patients with HIV-1 RNA > 1000 copies/ml (N = 1858) ABC/3TC* 600/300 mg QD + EFV 600 mg QD TDF/FTC* 300/200 QD + ATV/RTV 300/100 mg QD ABC/3TC* 600/300 mg QD + ATV/RTV 300/100 mg QD Sax PE, et al. IAC 2008. Abstract THAB0303.

Boosted PIs in ARV-Naive Patients: Which to use? *P <.05 HIV-1 es/ml ients With A < 50 copie (%) Pati RNA 100 90 80 70 60 ARTEMIS [3] (ITT) 48-Wk Noninferiority 84* 78* CASTLE [4] (ITT) 48-Wk Noninferiority i it 76 78 50 40 30 20 10 444n = 346 343 443 0 170 167 LPV/RTV DRV/RT LPV/RTV 400/100 BID 400/100 BID or 800/200 QD V 800/100 QD 440 ATV/RTV 300/100 QD Ortiz R, et al. AIDS. 2008;22:1389-1397.. Molina JM, et al. Lancet. 2008;372:646-655.

Eficacia de los ARV en pacientes naïve KLEAN 1 (ITT-E, TLOVR) 48 wk ALERT 2 GEMINI 3 ARTEMIS 4 (ITT, MD=F) (ITT) (ITT) 48 wk 48 wk 96 wk CASTLE 5 (ITT-CVR) 96 wk HIV RN NA <50 copie es ml (%) Non-inferiority Not powered* Interim analysis Superiority Non-inferiority 100 100 100 100 100 90 80 70 60 50 40 30 20 10 0 66 65 90 80 70 60 50 40 30 20 10 0 75 83 90 80 90 80 79 70 70 70 70 69 74 70,8 60 60 60 68 50 40 30 20 10 n=434 n=444 n=53 n=53 n=166 n=171 n=346 n=343 n=440 n=443 FPV/r LPV/r 700/100 400/100 BID BID FPV/r 1400/100 QD ATV/r 300/100 QD 0 SQV/r 1000/100 BID LPV/r 400/100 BID Neither FPV/r nor LPV/r QD are licensed in the EU. The EU licensed dose of DRV/r is 600/100 mg BID. *ALERT study was not powered for non-inferiority. Data in figures are from different studies and cannot be compared directly. 50 40 30 20 10 0 LPV/r DRV/r 800/200 800/100 BID /QD QD 90 80 50 40 30 20 10 0 ATV/r 300/100 QD LPV/r 400/100 BID 1. Eron J, et al. Lancet. 2006;368:476 482; 2. Smith K, et al. IAS 2007, Abstract WEPEB023; 3. Raffi F, et al. IAS 2007, Abstract WEPEB027; 4. De Jesus E, et al. ICAAC 2007, Abstract LBA H-718b; 5. Molina J-M, et al. Lancet. 2008;DOI:10.1016/S0140-6736(08)61081-8

5.-.and what about if I have side effects or virological failure?

Rescue Therapy in HIV infected patients Clinical Trials Clinical Trial Drug TORO Enfuvirtide RESIST. Tipranavir POWER. Darunavir DUET. Etravirine+Darunavir BENCHMRK. Raltegravir MOTIVATE Maraviroc

Patients with viral load <50 copies/ml (ITT-TLOVR): TLOVR): pooled 96-week analysis 100 90 ETR + BR (n=599) Placebo + BR (n=604) 80 Patients with viral loa ad <50 cop ies/ml (%) 70 60 50 40 30 20 10 61% 41% 60% 39% p<0.0001* 57% 36% 0 Baseline 2 4 8 12 16 20 24 32 40 48 56 64 72 84 96 Time (weeks) Mean change in CD4 cell count was 128 cells/mm 3 in the ETR + BR arm versus 86 cells/mm 3 in the placebo + BR arm (p<0.0001) 0001) *Logistic regression model controlling for baseline viral load, ENF use and study number ITT = intent-to-treat; TLOVR = time-to-loss of virological response algorithm

Week 48 Virologic Efficacy of New Drugs Defined as HIV-1 RNA < 50 c/ml Study Drug Regimen HIV-1 RNA TORO [1] RESIST [2] Enfuvirtide + OBR OBR alone Tipranavir + OBR Comparator PI + OBR < 50 copies/ml, % 18.3 7.8 22.8 10.2 POWER Darunavir/ritonavir + OBR 45.0 [3] Comparator PI + OBR 10.0 0 DUET [4,5] MOTIVATE [6] Etravirine + darunavir/ritonavir-containing OBR Placebo + darunavir/ritonavir-containing OBR 60.0 40.0 Maraviroc QD + OBR 41.8 Maraviroc BID + OBR 46.8 Placebo + OBR 16.1 BENCHMRK Raltegravir + OBR 63.0 [7,8] Placebo + OBR 33.0 1. Nelson M, et al. J Acquir Immune Defic Syndr. 2005;40:404-412. 2. Hicks CB, et al. Lancet. 2006;368:466-475. 3. Clotet B, et al. Lancet. 2007;369:1169-1178. 4. Haubrich R, et al. CROI 2008. Abstract 790. 5. Johnson M, et al. CROI 2008. Abstract 791. 6. Lalezari J, et al. ICAAC 2007. Abstract H-718a. 7. Cooper DA, et al. N Engl J Med. 2008. In press. 8. Steigbigel R, et al. N Engl J Med. 2008. In press.

Is there a possibility to speed up this process? cy ) Frequenc (IUPM) 10000 1000 100 10 1 01 0.1 0.01 0.001 0.00010001 0.00001 - t 1/2 = 44.2 months Time to eradication > 73 y Siliciano R, et al. 0 1 2 3 4 5 6 7 8 Time on HAART (years) Time needed for eradication estimated as 73.4 years!, however it might take only up to 7,7 years of continuous therapy in individuals who initiate HAART early in HIV infection (0.3-4.4 4 months after the initiation of symptoms of primary HIV infection) Chun T-W et al. JID 2007;195:1762-4

6.- What about the future? What about the challenges?

ARV Therapy 2010,... and THE FUTURE. - More convenience-well tolerated regimens - New drugs available: - PI: Darunavir - NNRTI: Etravirine - Integrase inhibitors: Raltegravir - CCR5 antagonists: Maraviroc - New concept: Detectable is unacceptable - Revisiting the concept of eradication

ARV Therapy: Challenges-2010 Avoid new cases: Prevention Cure (eradication) Active vaccine Epidemic trends in developing countries

Public Health issues and HIV treatment If an HIV infected person has an undetectable VL can they transmit HIV to their partner? Can we treat our way out of the epidemic? Would expanding HAART to everyone diagnosed with HIV with a CD4 count below 350 cells/mm 3 together with prevention strategies, have a pronounced effect on transmission, by reducing viral load at a population p level. HIV Transmission under ART. XVII International AIDS Conference, Mexico City, SUSAT41, 2008. Wasserfallen FM Swiss statement for PLWHA on effective ARV treatment. XVII International AIDS Conference, Mexico City, abstract MOPE0212, 2008,Lima VD et al.j Infect Dis 198 (online edition), 2008.

COSTE MENSUAL EN EUROS DE LOS TARV DISPONIBLES (PVL + 4% IVA). Hospital Clínic. Año 2010 T-20 90 mg c/12h MVC 1 comp c/12h RAL 400 mg c/12h TPV/r 500/200 c/12h DRV/r 600/100 mg c/12h DRV/r 800/100 mg c/24h ATV/r 300/100 mg c/24h ATV 400 mg c/24h LPV/r 2 comp c/12h FPV/r 700/100 mg c/12h SQV/r 1000/100 mg c/12h SQV/r 1500/100 mg c/24h RTV 100 mg c/12h ETR 200 mg c/12h EFV 600 mg c/24h NVP 200 mg c/12h Atripla 1 comp c/24h Trizivir 1 comp c/12h Truvada 1 comp c/24h Kivexa 1 comp c/24h Combivir 1 comp c/12h TDF 245 mg c/24h ABC 300 mg c/12h ddi 400 mg c/24h FTC 200 mg c/24h 3TC 300 mg c/24h d4t 40 mg c/12h d4t 30 mg c/12h AZT 300 mg c/12h ddi 250 mg c/24h 468 478 454 416 376 362 260 47 468 276 208 510 450 370 302 300 235 160 153 147 146 142 108 100 718 713 729 832 827 1586 0 200 400 600 800 1000 1200 1400 1600 1800

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